Background

Metformin is usually prescribed as first line therapy for type 2 diabetes mellitus (DM2). However, the benefits and risks of metformin may be different for older people. This systematic review examined the available evidence on the safety and efficacy of metformin in the management of DM2 in older adults. The findings were used to develop recommendations for the electronic decision support tool of the European project PRIMA-eDS.

Methods

The systematic review followed a staged approach, initially searching for systematic reviews and meta-analyses first, and then individual studies when prior searches were inconclusive. The target population was older people (≥65 years old) with DM2. Studies were included if they reported safety or efficacy outcomes with metformin (alone or in combination) for the management of DM2 compared to placebo, usual or no treatment, or other antidiabetics. Using the evidence identified, recommendations were developed using GRADE methodology.

Results

Fifteen studies were included (4 intervention and 11 observational studies). In ten studies at least 80% of participants were 65 years or older and 5 studies reported subgroup analyses by age. Comorbidities were reported by 9 studies, cognitive status was reported by 4 studies and functional status by 1 study. In general, metformin showed similar or better safety and efficacy than other specific or non-specific active treatments. However, these findings were mainly based on retrospective observational studies. Four recommendations were developed suggesting to discontinue the use of metformin for the management of DM2 in older adults with risk factors such as age > 80, gastrointestinal complaints during the last year and/or GFR ≤60 ml/min.

Conclusions

On the evidence available, the safety and efficacy profiles of metformin appear to be better, and certainly no worse, than other treatments for the management of DM2 in older adults. However, the quality and quantity of the evidence is low, with scarce data on adverse events such as gastrointestinal complaints or renal failure. Further studies are needed to more reliably assess the benefits and risks of metformin in very old (>80), cognitively and functionally impaired older people.

Type 2 diabetes mellitus (DM2) is a prevalent chronic disease worldwide. Around 9% of adults have DM2, increasing to more than 20% of those aged 65 years or older [1, 2]. DM2 and its complications are an important cause of morbidity, and people with DM2 have substantially reduced life expectancy [3]. Duration of DM2 and degree of metabolic control are important factors determining the prognosis for people with DM2 [4]. However, the use of drugs for managing DM2 has been associated with preventable drug-related causes of admission to emergency units in older populations [5, 6, 7].

Metformin is one of the most widely prescribed first and second line oral glucose-lowering drugs. While it has low risk for hypoglycaemia, the risk for gastrointestinal effects is higher and it is contraindicated in patients with renal insufficiency [8, 9, 10]. Renal function declines with age and, therefore, should be monitored closely in older adults who are prescribed metformin [11, 12]. Clinical guidelines (in the United Kingdom, Canada and Australia) have advised that the use of metformin is contraindicated, or that lower doses be used, depending on renal function [13]. The use of metformin has also been associated with a higher risk of lactic acidosis but this has not been widely reported [14].

Currently, there is little empirical data about patient safety and effectiveness data on to the use of oral antidiabetics including metformin among older adults. Evidence-based clinical guidelines for the treatment of DM2 have acknowledged the lack of direct evidence in older people [10]. STOPP/START criteria version 2 considered metformin as a potentially inappropriate medication for older people with severe renal failure [15]. Inappropriate prescribing may involve the prescription of a wrong dose, the lack of a clear indication or the lack of evidence-base, among others [16].

The objectives of this systematic review (SR) are:

to identify and collect existing literature on the risks and benefits of use of metformin in the treatment of DM2 in older adults,

to assess the quality of the evidence identified, and develop recommendations when to discontinue or to adjust the dose of metformin in the treatment of DM2 in older adults.

This evidence was used to develop recommendations on discontinuation or dose adjustment of metformin in older people for the management of DM2 in order to reduce potentially inappropriate prescribing. These recommendations will be used in the electronic decision support tool of the “Polypharmacy in chronic diseases: Reduction of Inappropriate Medication and Adverse drug events in elderly populations by electronic Decision Support” (PRIMA-eDS) project [16].

This systematic review was developed following the methods proposed by both the Cochrane Handbook for Systematic Reviews of Interventions [17] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [18]. A full description of the methods has been published previously [19].

Study inclusion criteria

Types of studies

We included systematic reviews, meta-analyses, controlled interventional studies and observational studies reporting on risks and benefits of the use of metformin in the treatment of DM2 in older adults. We excluded abstracts, pooled analyses, editorials, opinion papers, case reports, case series, narrative reviews, letters, and qualitative studies.

Types of participants

The population of interest were older people with DM2. We considered the age of 65 as cut-off point for defining older people, which has been traditionally used because of its association with retirement age in some developed countries [20, 21, 22]. The criteria for inclusion in this systematic review were:

For existing systematic reviews and meta-analyses:

overall mean or median age ≥ 65 years; or

overall mean or median age

overall mean or median age not reported but 80% or more of the included studies reporting a mean or median age ≥ 65 years.

<80% of participants ≥65 years with subgroup analysis reporting on participants ≥65 years.

Types of interventions

Studies reporting on the efficacy and/or safety of metformin for the management of DM2 were included irrespective of whether metformin was prescribed as monotherapy or in combination with any other. Included studies compared metformin versus placebo, usual or no treatment, and other drugs to treat DM2 or a non-pharmacological intervention.

Chukka 3 Women's 12 67 SeaVees Olive Eye Types of outcomes

The following clinically relevant endpoints were included either as primary or secondary outcomes:

Quality of life

Mortality

Life expectancy

Hospitalisations

Cognitive impairment or cognitive status

Functional impairment or status

Cardiovascular event including stroke

Renal failure

Composite end points including any of the above (extraction of individual outcomes was undertaken if reported by original studies)

Adverse drug event including hypoglycaemia

Any of the above evaluated as safety endpoints.

Studies evaluating only glycaemic control or lactate levels. To aid interpretation of findings outcomes were classified into two tiers according to their anticipated impact on longer-term health and quality of life: Tier 1 outcomes have shorter-term impact including hypoglycaemia and adverse events (including serious adverse events); tier 2 outcomes have longer-term impact including, but not limited to, cardiovascular and cerebrovascular events, related admissions, and death.

Setting

All settings were included.

Language

Language restrictions were not applied for study searches. However, the inclusion of studies was restricted to languages that could be read by the research team English, German, Finish, Italian, and Spanish.

Search method

Database searches were conducted by YVM and AW following staged methodology comprising four sequential literature searches. Each search being performed only if the preceding one yielded high quality results or if evidence insufficient to enable any evidence based recommendations to be made. Each search was conducted on 09 December 2015 using the OVID interface for each database. The searches included the following databases and types of studies:

Search 1: Systematic reviews and meta-analyses in the Cochrane database of Systematic Reviews (2005 to 2015) and the Database of Abstracts or Reviews of Effects (1991 to 2015).

References of included studies were checked to identify further articles for inclusion, and we also considered studies identified from manual searches and snowballing. Protocols for yet-to-be published studies were collected to inform future updates of this systematic review. Studies excluded after full-text check are listed in Additional file 1 together with reasons for exclusion.

The PICOS-framework was used to develop the search terms (population: older people, intervention: metformin, comparison: no limits, outcomes: see list above “Types of outcomes” and study design: systematic reviews, meta-analyses, controlled interventional studies and observational studies). We also developed search filters specific for different study designs, described in detail in the protocol [19]. Additional file 2 lists the full search terms for each search (i.e. search 1, 2 and 3B).

Data management

Selection of studies

Two reviewers assessed titles and abstracts from each search independently to identify studies to consider for inclusion. Full manuscripts were then obtained for all titles and abstracts meeting the inclusion criteria or where there was any uncertainty about inclusion. YVM, ARG, CA, BF, CS and LS were involved in this task.

Reviewers discussed any disagreement about studies to include. AS was consulted when YVM and ARG could not reach an agreement on whether or not to include a study. YVM and ARG were consulted when CA, CS, BF and LS could not reach agreement.

Data extraction

YVM, ARG, CA, BF, CS and LS (reviewers) independently conducted data extraction of the included studies using a standardised and piloted data collection form previously published with the protocol [19]. This extraction form included information related to the study design and aim, characteristics of participants (i.e. age, sex, setting, comorbidity, use of concomitant medications, functional status, and cognitive status), the intervention (i.e. metformin) and comparison, time to follow-up, and reported outcomes. Completeness and accuracy of data extraction was then double-checked by a second reviewer.

Quality appraisal

For each study design we used separate validated assessment tools to evaluate quality (AMSTAR) [23, 24] was used for systematic reviews/meta-analyses, for intervention studies the Cochrane Collaboration’s tool for assessing risk of bias [17] was used, and for observational studies the Critical Appraisal Skills Programme (CASP) [25, 26].

Dealing with duplicate and companion publications

All relevant data from publications relating to a single primary study were included. The staged approach carries a risk of ‘double counting patients whose trials are included in a systematic review. Any such instances have been identified, reported and corrected for in our data synthesis.

Data synthesis

A narrative synthesis describing all included systematic reviews, meta-analyses, intervention and observational studies, participants and findings was carried out. The included studies were highly heterogeneous in comparison treatments, length of follow-up, type of design, and definition of outcomes; therefore no additional meta-analyses were performed. The quality of the included studies is also reported.

Identification of “references of interest” for the development of recommendations

During the search process, reviewers identified additional references which did not fulfil the inclusion criteria of the SRs but which they considered of interest for the development of recommendations according to the methodology described by Martinez-Renom Guiteras (2016) [19].

Development of recommendations

Included studies and references of interest were summarised in a document used by the research team to develop and discuss recommendations to discontinue the use of metformin for the management of DM2 in older people including: a) study design or type of reference, target population and sample size, metformin dose (if available) and comparison groups, outcomes, main results, subgroup analysis if applicable; b) quality appraisal ratings of included studies; and c) proposed recommendations. Each recommendation was given a strength (weak or strong) and quality (low, moderate or high) rating following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology [27, 28, 29]. Recommendations were written following a standardised schema and reflecting the strength and the quality of the evidence. The Finnish team of editors from Duodecim Medical Publications Ltd. participated in the later stages and approved the recommendations.

Results of the search

Searches 1, 2, 3A and 3B were all conducted. Search 1 identified one relevant meta-analysis, by Lamanna et al. [30] which did not provide summary results for our SR targeted at old age and was excluded. However eligible individual studies were identified from it and added to search 3A. The date of the search by Lamanna (2011) [30] was used as the start date for our search for additional individual studies under search 3B. No relevant meta-analyses were identified from search 2.

In total 2185 records were found through initial database searching (126 from search 1, 175 from search 2, 1884 from search 3B). Additionally, we identified 66 records from search 3A (individual studies from excluded systematic reviews and meta-analyses) and 461 records from reference lists of included studies. After removing duplicates, we screened 2318 records and excluded 1878 checking titles and abstracts. We assessed 440 full-texts for eligibility and excluded 425. Main reasons for exclusion were wrong population, wrong intervention and wrong outcome. We included 15 studies reported by one publication each. The PRISMA flow diagram is presented in Fig.
1.

To investigate whether the safety and efficacy benefits of initiating insulin therapy with glargine and continued OADs, versus switching to premixed insulin, as previously reported, were also observed in the subset of patients aged 65 and older.

To assess the relationship between the prescription of insulin-sensitizing agents (metformin and/or TZD) and death or readmission ofelderly diabetic patients initially admitted with heart failure in a cohort derived from the National Heart Care Project (NHC).

P: 5296

P ≥ 65 years: 5296

P using metformin: 1861

P using TZD: 2226

P using no insulin sensitizer: 12,069

1 year

Time from hospital discharge to death due to any cause, time to first readmission for any cause or for heart failure, proportions of patients who died or were readmitted at least once in the year after discharge, rates of readmission for the primary diagnosis of metabolic acidosis.

To assess whether metformin use was associated with difference in mortality after adjustment for baseline differences and for the propensity to receive metformin among diabetics with established coronary artery disease, cerebrovascular disease, or peripheral arterial disease.

P: 19,553

P ≥ 65 years: 12,649

P using metformin: 4389

P without metformin: 8260

2 years

2-year all-cause mortality. Cardiovascular death and first-occurring event among death, MI, or stroke.

To determine the association between TZD use and fracture risk among older adults with DM2.

P: 20,291

P ≥ 65 years: 20,291

P using TZD: 2347

P using SU: 13,709

P using metformin: 4235

Follow-up ended at the first of any of the following events: death, loss of eligibility for Medicare or the drug benefit program, 180 days after the last dosage of oral hypoglycaemic agent, or end of follow-up.

bThe sum of patients in each subgroup is greater than the number of participating patients, as the study design allowed patients to take different drugs at different time periods

cSAEs comprised any experience that was fatal, life-threatening, permanently or substantially disabling, resulted in permanent or significant disability or incapacity, required or prolonged hospitalization, an important medical event that jeopardized the patient or required intervention to prevent a serious outcome, a congenital abnormality, a cancer, an overdose of medication, or a condition that resulted in the development of drug dependency or drug abuse

Representation of males ranged from 24.1% [44] to 97% [41]. Eight studies reported ethnicity with most participants being white/Caucasian (up to 81%) [37]. Participants from four different continents were involved in the studies including America (n = 8), Europe (n = 7), Asia (n = 3) and Australia (n = 2). Comorbidities were reported in 11 studies, and congestive heart failure, myocardial infarction, hypertension, chronic kidney disease and hypothyroidism were the most commonly reported. Functional status was reported in one study [37]. No studies reported on the frailty level of the participants. Cognitive status was reported in four studies [37, 38, Forever Buckle Heel Strap Booties Tan 62 Block Ankle Women's r5xwAr, 40]. The percentage of participants with dementia was low in most studies ranging from 2.8% [38] to 67% [37]. Participant characteristics are summarised in Additional file 3: Table S1.

Covariates in models

Adjustment for relevant covariates is important in observational studies to reduce confounder bias. The use of covariates indicates that a study’s authors have considered this issue, although by no means implies that bias has been eliminated. Many of the studies used long lists of covariates, therefore Additional file 3: Table S2 is given for online publication.

Interventions and outcomes

Most of the included studies investigated the effect of metformin as monotherapy [33, 37, Forever Buckle Heel Strap Booties Tan 62 Block Ankle Women's r5xwAr, 40, 41, 42, 44, 45]. We classified comparison treatments as either “non-specific active treatments” (the comparator was not a single specific drug or treatment e.g. usual care, no insulin sensitizer, not on metformin), or as “specific active treatments” (the comparator was a specified treatment such as insulin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, and other specific drugs and combinations).

Main findings

Table
2 summarises the results for each study for both metformin and comparison groups, with estimated risk ratios with 95% confidence intervals, together with statistical comparisons from the study. The results are organised by type of outcome (safety or efficacy), and then by type of comparator within each type of outcome (metformin against non-specific active treatments; metformin against other specific active treatments). A Additional file
3: Table S2 is available with the covariates that were taken into account in the statistical models of the included studies.

Y yes; N no; U unclear; NA not applicable. Items 11 and 12 are part of the findings in Table 2

Additional references of interest for the development of recommendations

One further reference was incorporated as additional reference of interest for the development of the recommendations [46]. A clinical guideline from the American Geriatrics Society which included recommendations about the management of DM2 in older people with renal insufficiency [46] was included as an additional reference of interest for the development of recommendations.

Four recommendations about stopping the use of metformin in older people with DM2 (Table
5) were developed related to halting In order to discuss and agree on these recommendations three meetings took place between YVM (researcher) and ARG (researcher and clinician). IK (senior clinician and researcher) and AS (senior clinician and researcher) participated in one of these meetings. The whole body of evidence identified in the SR was taken into consideration for the development of the recommendations. However, each recommendation was specially supported by the following specific studies included in the SR or considered as additional references of interest: a clinical guideline, an observational study without high quality [
42] and two randomised trials with insufficient information to assess their risk of bias [
Women's Tan Dingo Slouch Boot Olivia dIvgqwOHvr,
43]. All recommendations were considered to be weak and based on evidence of low quality, and the reasons for this are reported in Table
5. The recommendations were included in the Comprehensive Medication Review (CMR) tool developed as part of the PRIMA-eDS project, and they were formulated according to their strength and the quality of their evidence [
19].

Table 5

Recommendations to stop the use of metformin in older people with type 2 Diabetes mellitus

Recommendations

Strength of the recommendation

Quality of the evidence

Type of evidence

It is suggested to discontinue metformin for the management of type 2 diabetes mellitus in patients with 2 or more of the following risk factors: age > 80; gastrointestinal complaints during the last year; GFR ≤60 ml/min. The benefit of metformin in this patient is uncertain and it is possibly outweighed by the risk of adverse drug reactions, depending on their severity.

It was considered to downgrade the quality of the evidence to low quality because there were study limitations (1 observational study with limitations and 2 RCTs with unclear risk of bias), indirectness (observational study with subgroup analysis), inconsistency (different types of comparisons evaluated).

It is suggested to discontinue metformin for the management of type 2 diabetes mellitus in patients 80 years and older taking the life expectancy, physical and functional status of the patient into account. Patients who are concerned about adverse events or appear to experience AE may reasonably choose not to take metformin.

It was considered to keep the quality of the evidence as low quality because this observational study had limitations: data in older people was from subgroup analysis, lack of reporting on recruitment and confounding factors.

It is suggested to discontinue metformin for the management of type 2 diabetes mellitus in patients with gastrointestinal complaints taking the possible benefit and the severity of the patient complaints as possible dverse drug reactions into account.

Reason: small RCTs with low quality and no significant benefits with metformin; uncertainty about the magnitude of the benefits and harms.

It was considered to downgrade the quality of the evidence to low quality because there were study limitations (2 RCTs with unclear risk of bias) and inconsistency (different types of comparisons evaluated).

It is suggested to discontinue metformin for the management of type 2 diabetes mellitus in patients with renal insufficiency because metformin may increase the risk of lactic acidosis.

Our aim was to systematically review the existing evidence on the risks and benefits of the use of metformin for the management of DM2 in older people. We therefore included only those studies where a high proportion of participants were aged 65 years or older, as specified in our inclusion criteria. No systematic review or meta-analysis fulfilled our inclusion criteria, and we finally included 4 RCTs and 11 observational studies, with most observational studies being retrospective.

When comparing metformin with sulfonylureas, results suggest that metformin may be better than sulfonylureas in reducing several outcomes such as cardiovascular outcomes, mortality, hospitalisation for hypoglycaemia, or risk of falls in people aged 65 and older with DM2 [Rainbow Chief Sneaker Girls Glitter Western wFq64On, 33, 37, 41, 45]. When comparing metformin with no insulin sensitizer antidiabetic drugs, divergent results were found depending on the study population [34, Forever Buckle Heel Strap Booties Tan 62 Block Ankle Women's r5xwAr] Generally, these results are in line with clinical guidelines recommending metformin as the first-line drug treatment for adults with DM2 [10]. Guidelines also suggest that if initial drug treatment with metformin fails to control levels of glycated haemoglobin, dual therapy should be considered [10]. Only one study was identified which specifically analysed risks and benefits of combining metformin with other antidiabetic drugs, where risk of hypoglycaemia with the combination of metformin, sulfonylurea and insulin glargine compared to premixed insulin was decreased [Pegasus T Girls' Nina Black Patent Sq4nUw]. Thus, there seems to be a lack of evidence analysing the benefits and risks of combined therapy including metformin in older people with DM2.

The benefits of metformin on the mortality of very old people (aged 80 years over) were investigated by only one included study [42]. Here, mortality was significantly decreased with the use of metformin in people aged 65–80 but the effect was not significant for the population aged 80 and older. The study could been underpowered for this subgroup analysis, but evidence this may also suggest that the benefits of metformin on mortality may be non-existent for very old people, especially those with limited life expectancy, as suggested by other authors [47].

The included studies rarely reported on the functional level and cognitive status of the participants; the use of concomitant drugs and the presence of other diseases were more frequently reported but focused mostly on cardiovascular drugs and diseases. Thus, the present systematic review demonstrates that not only very old people, but also cognitively and functionally impaired people and old people with multimorbidity are underrepresented or at least underreported in existing studies, which limits the generalisability of already scarce evidence for this heterogeneous group of older people. A growing body of literature presents functional and cognitive status as well as multimorbidity as predictors of mortality among older people independently from their chronological age [48, 49, 50], which supports the idea that further studies analysing these aspects are necessary.

Although the lack of evidence has been previously commented on by several authors [1, 47, 51], to the best of our knowledge, ours is the first study to systematically review all available evidence on the risks and benefits of metformin for the management of DM2 in older people.

None of the other studies reported their target glycaemic control level clearly. It would be useful for future studies on the management of DM2 to report the target glycaemic control level, especially for frail older people.

Our research team developed four recommendations using both the results of the systematic review and the additional references identified [Women's Tan Dingo Slouch Boot Olivia dIvgqwOHvr, 42, 43, 46]. The recommendations advise clinicians to consider discontinuing metformin in people aged 80 and older, those with gastrointestinal complaints during the last year, and/or those with Glomerular Filtration Rate (GFR) ≤60 ml/min. These recommendations have been incorporated in the trial version of an electronic decision support tool that aims to help general practitioners to reduce inappropriate prescriptions for older people with multimorbidity. Decisions on prescription or de-prescription of metformin should be made taking the symptoms and individual characteristics of each patient into account and clinicians receive instructions on that. Currently, the tool is being tested in a cluster randomised controlled trial in four European countries [53].

This systematic review has limitations. The search strategy and inclusion criteria were designed to identify studies focusing on older people; studies on the general population that may have contained relevant information for the older population might have been overlooked. However, using independent reviewers for study selection and our peer reviewed process of development of recommendations should have minimised this problem. Our recommendations focus only on the discontinuation of metformin, as it was not the aim of the PRIMA-eDS project to develop recommendations when to use metformin. Nevertheless, this systematic review aims at providing an overview of the existing evidence on both the benefits and risks of the use of metformin in older people.

This study highlights the lack of good quality evidence on the risks and benefits of metformin for the management of DM2 in older people. The use of metformin seems associated with benefits to lower mortality risk in older people, and may also be associated with a reduced risk of adverse events such as hypoglycaemia and non-fatal cardiovascular events, than other antidiabetic drugs, especially sulfonylureas. However, no prospective studies focussing on very old (80 and older) and functionally and cognitively impaired older people are available. In very old people, those with renal insufficiency (GFR ≤60 ml/min) and those with gastrointestinal complaints during the last year, the discontinuation of metformin should be considered, especially for those with limited life expectancy or functional impairment. There is an urgent need for studies on the risks and benefits of metformin for the management of DM2 in these populations in order to guide clinicians in planning of individualised patient care.

Acknowledgements

We would like to thank Annette Barber at the University of Manchester for her support conducting the database searches and providing full-texts when publications were not freely available.

Funding

The PRIMA-eDS study was supported by a grant from the European Commission within the 7th Framework Programme (Grant No. 305388–2). The work of YVM was also supported by a grant from the NIHR Greater Manchester Primary Care Patient Safety Translational Research Centre.

Publication of this article was funded by the UK National Institute for Health Research School for Primary Care Research, University of Manchester.

Availability of data and materials

The data supporting the conclusions of this article is included within the article (and its additional files).

About this supplement

This article has been published as part of BMC Geriatrics Volume 17 Supplement 1, 2017: The Evidence Base of Frequently prescribed drugs in older Patients: A series of systematic reviews as a basis for recommendations in the PRIMA-eDS-tool to reduce inappropriate polypharmacy. The full contents of the supplement are available online at https://bmcgeriatr.biomedcentral.com/articles/supplements/volume-17-supplement-1.

Authors’ contributions

AS, ARG and YVM conceptualised the study. YVM, ARG, CA, BF, CS, TAQ, AW and LS selected the included studies. YVM, ARG, CA, BF, CS and LS extracted data and conducted quality appraisal. ARG and YVM prepared the recommendation to be discussed with AS and IK. LS, YVM, ARG, and CA drafted the manuscript, supported by DR and AS. All the authors critically reviewed the drafts and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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